rs1141608

Positions:

• chrX-149501018-G-A
• chrX-149501018-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000202.8(IDS):​c.438C>T​(p.Thr146=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.344 in 1,165,083 control chromosomes in the GnomAD database, including 54,181 homozygotes. There are 119,286 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T146T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.31 (4367 hom., 9370 hem., cov: 22)
  • Exomes 𝑓: 0.35 (49814 hom. 109916 hem.)
• Consequence: IDS NM_000202.8 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.771

Genes affected

IDS (HGNC:5389): (iduronate 2-sulfatase) This gene encodes a member of the sulfatase family of proteins. The encoded preproprotein is proteolytically processed to generate two polypeptide chains. This enzyme is involved in the lysosomal degradation of heparan sulfate and dermatan sulfate. Mutations in this gene are associated with the X-linked lysosomal storage disease mucopolysaccharidosis type II, also known as Hunter syndrome. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant X-149501018-G-A is Benign according to our data. Variant chrX-149501018-G-A is described in ClinVar as [Benign]. Clinvar id is 92619.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-149501018-G-A is described in Lovd as [Likely_benign]. Variant chrX-149501018-G-A is described in Lovd as [Likely_pathogenic]. Variant chrX-149501018-G-A is described in Lovd as [Pathogenic]. Variant chrX-149501018-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.771 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.386 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IDS	NM_000202.8	c.438C>T	p.Thr146=	synonymous_variant	4/9	ENST00000340855.11
IDS	NM_001166550.4	c.168C>T	p.Thr56=	synonymous_variant	4/9
IDS	NM_006123.5	c.438C>T	p.Thr146=	synonymous_variant	4/8
IDS	NR_104128.2	n.607C>T		non_coding_transcript_exon_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IDS	ENST00000340855.11	c.438C>T	p.Thr146=	synonymous_variant	4/9	1	NM_000202.8	P1

Frequencies

GnomAD3 genomes AF: 0.312 AC: 34181 AN: 109470 Hom.: 4371 Cov.: 22 AF XY: 0.294 AC XY: 9358 AN XY: 31862

Gnomad AFR AF: 0.252

Gnomad AMI AF: 0.407

Gnomad AMR AF: 0.250

Gnomad ASJ AF: 0.331

Gnomad EAS AF: 0.00283

Gnomad SAS AF: 0.0690

Gnomad FIN AF: 0.299

Gnomad MID AF: 0.433

Gnomad NFE AF: 0.390

Gnomad OTH AF: 0.325

GnomAD3 exomes AF: 0.275 AC: 50217 AN: 182867 Hom.: 5441 AF XY: 0.273 AC XY: 18400 AN XY: 67351

Gnomad AFR exome AF: 0.255

Gnomad AMR exome AF: 0.157

Gnomad ASJ exome AF: 0.334

Gnomad EAS exome AF: 0.00115

Gnomad SAS exome AF: 0.0903

Gnomad FIN exome AF: 0.317

Gnomad NFE exome AF: 0.391

Gnomad OTH exome AF: 0.307

GnomAD4 exome AF: 0.347 AC: 366356 AN: 1055561 Hom.: 49814 Cov.: 25 AF XY: 0.328 AC XY: 109916 AN XY: 335471

Gnomad4 AFR exome AF: 0.245

Gnomad4 AMR exome AF: 0.165

Gnomad4 ASJ exome AF: 0.336

Gnomad4 EAS exome AF: 0.00110

Gnomad4 SAS exome AF: 0.0926

Gnomad4 FIN exome AF: 0.318

Gnomad4 NFE exome AF: 0.392

Gnomad4 OTH exome AF: 0.322

GnomAD4 genome AF: 0.312 AC: 34176 AN: 109522 Hom.: 4367 Cov.: 22 AF XY: 0.294 AC XY: 9370 AN XY: 31922

Gnomad4 AFR AF: 0.252

Gnomad4 AMR AF: 0.249

Gnomad4 ASJ AF: 0.331

Gnomad4 EAS AF: 0.00283

Gnomad4 SAS AF: 0.0681

Gnomad4 FIN AF: 0.299

Gnomad4 NFE AF: 0.390

Gnomad4 OTH AF: 0.319

Alfa AF: 0.340 Hom.: 6734

Bravo AF: 0.308

EpiCase AF: 0.397

EpiControl AF: 0.393

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 08, 2013	- -

Mucopolysaccharidosis, MPS-II Benign:4

Benign, criteria provided, single submitter	research	IIFP, CONICET-UNLP	May 31, 2007	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 08, 2016	Variant summary: The IDS c.438C>T (p.Thr146Thr) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. 5/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 24360/87524 control chromosomes (including 2605 homozygotes and 9302 hemizygotes) at a frequency of 0.2783237, which is approximately 96 times the estimated maximal expected allele frequency of a pathogenic IDS variant (0.0028868). Thus this variant is a common polymorphism found in the general population. In addition, multiple clinical diagnostic laboratories have classified this variant as benign and the variant is considered a common polymorphism in the literature. Taken together, this variant is classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 25, 2018	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 03, 2016	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 24, 2014

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	1.5
DANN	Benign	0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1141608; hg19: chrX-148582549; COSMIC: COSV61712415; COSMIC: COSV61712415;